Neurons possess ion channels that are directly activated by voltage, ligands, temperature, and mechanical forces, but not by light. Our goal in this project is to use a combination of organic chemistry and molecular biology to engineer new types of ion channels that can be directly regulated by light. We will then use these channels to answer questions focused on activity dependent synaptic plasticity in the retina that are unapproachable with presently available methods. Specifically, this project will make several major contributions. 1) It will add to the growing toolbox of light-activated channels that are of great utility for remote control of different aspects of neuronal activity. 2) It will elucidate whether retinal ganglion cells, like hippocampal neurons, exhibit homeostatic synaptic plasticity, revealing whether synapses in the retina are hard-wired or can change with use. 3) It will elucidate whether synaptic homeostasis operates locally within a portion of a dendritic tree, or only globally, across an entire neuron, providing clues as to the functional importance and mechanism of homeostatic plasticity in the hippocampus and retina. 4) It will elucidate the changes in the physiology of the retinal circuit that occur as a consequence of photoreceptor degeneration in mouse and rat models of retinitis pigmentosa. By elucidating the functional effects and time course of retinal remodeling, this study will provide information of key importance for evaluating and designing new therapeutic strategies that rely on intact synaptic signaling through the retina, including gene therapy for restoring photoreceptor function and stem cell therapy for regenerating rod or cones. PUBLIC HEALTH RELEVANCE: In this project we will engineer new molecules that will allow nerve cells to be turned on and off with light. We will use these tools to answer important questions about how synaptic connections between nerve cells change with activity and how signaling through the retina changes after rods and cones are lost during degenerative blinding diseases such as retinitis pigmentosa. This will provide fundamental information for understanding how the retina functions and adapts to different light conditions and will be useful for designing and evaluating future therapeutic strategies for restoring vision.